The objectives of this study are to establish the in vivo role of mouse natural killer (NK) cells in protection against tumor growth and as a possible regulator of normal stem cell differentiation. The significance of NK cells in the "hybrid resistance" phenomenon in rejection of transplantable tumor lines and in protection against primary tumor induction will be analyzed by three different models: 1) Congenic resistant (CR) and H-2 recombinant strains will be used to further analyze the H-2 linked genetic control of NK activity and in vivo tumor resistance. 2) T-cell depleted mice will be used to evaluate the relative role of T-cell dependent versus NK mediated mechanisms in in vivo tumor resistance. 3) The mouse mutant beige, recently found to selectively lack NK activity but with normal T-cells and macrophages, will be used as a unique possibility to study the importance of NK cells in immune surveillance against tumors. The second part of this application deals with the existence of "natural" targets for NK cells in thymus and bone marrow, and their relationship with the host NK system. The previously reported inverse relationship between the occurrence of these natural targets and the NK system of the host will be analyzed, and the natural targets characterized. The last part of the application is based on a previous demonstration of natural antibodies in rabbits directed against specificities associated with the "target structure" for mouse NK cells on tumor lines. The biological significance, the specificity and the usefulness of these "NK associated" natural antibodies in analyzing the specificity of mouse NK cell will be investigated.